Anapharm-Designing Safe and Efficient Phase 1 Studies

Designing Safe and Efficient Phase I Studies to Expedite Clinical Development
Mario Tanguay, B.Pharm, Ph.D. Vice President, Scientific & Regulatory Affairs, Anapharm Guest Professor, Faculty of Pharmacy, University of Montreal April 12, 2010
The views expressed herein are solely those of the author and do not necessarily reflect the official policy, position or opinions of PharmaNet Development Group, Inc. and its affiliates
2010 PharmaNet Development Group, Inc. All rights reserved.
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Agenda Introduction
Are you ready to go to Phase I Objectives of Phase I studies
Study Design Issues

Recent trends will be presented based on some FIH studies conducted at Anapharm over the last 2 years (n=27) Determination of maximum recommended starting dose Study population (age, inclusion of females) Sample size considerations Dose escalation scheme
Attempts To Make Phase I Programs More Efficient

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Are You Ready to Move to Phase I

There is often a lot of pressure on the development teams to obtain data in humans (and proof of concept) as quickly as possible For that reason, Phase I formulation development is often neglected (or simply delayed to a later date) The challenge: ~60% of NCE in development are poorly soluble1 (poor solubility = dissolution problems, poor and/or erratic absorption ) The risk: clinical testing may be initiated with a less than optimal formulation for which reliability, reproducibility and scalability are not fully understood
1) H. Dubin, Drug Del. Technol., 2006
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Using a Non Optimal Formulation in FIH Case Example
Less than proportional increase in AUC due to solubility issue No real conclusion can be drawn about safety data and MTD
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Formulations Used in Recent Studies Done at Anapharm
Powder in a bottle used in almost 50% of studies with oral administration

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Are You Ready to Move to Phase I

So poorly soluble and/or poorly permeable drugs should require more attention before moving quickly to Phase I Biopharmaceutical properties must be taken in consideration
BCS classification
Neglecting those aspects can make the results from the FIH study useless
No clear demonstration of MTD if a plateau in bioavailability is reached May not reach systemic exposure required for the desired pharmacological effect
Some possible advantages of a good Phase I formulation strategy

Enhance the bioavailability of the compound Reduce the effect of flood Decrease PK variability Ensure scalability to manufacture batch size
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Objectives of Phase I Trials

Determination of safety and tolerability To identify suitable dose or dose range for further studies Pharmacokinetics of the drug There is also a trend for adding various objectives in order to obtain more information earlier in drug development process: Effect of food Drug-drug interactions Absolute bioavailability Effect on biomarkers Proof of concept in either healthy or patient populations Etc.
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Determination of Maximum Recommended Starting Dose

FDA proposed a methodology (based on NOAEL) to be used to determine the maximum recommended starting dose (MRSD) in FIH However, other factors should be considered, especially in the case of high risk compounds (EMEA Guidance, FIH trials), such as:
Drugs affecting immune system Drugs with novel mode action Drugs with steep dose-response relationship When there is little knowledge about the nature of the target When available animal models are of questionable relevance
In that context, calculation of MABEL (the minimal anticipated biological effect level) may be warranted Special attention to PK/PD data
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Determination of Maximum Recommended Starting Dose

Recent trends observed for studies conducted at Anapharm
NOAEL: safety factor of 10 was applied about 40% of the time A more conservative safety factor was otherwise used (up to 300)
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Study Population
Trend to involve patients earlier in the clinical development, but healthy volunteers are still generally enrolled in single ascending dose (SAD) phase, unless unsafe or unethical Phase I studies may include cohorts of target populations, but more often in the multiple ascending dose (MAD) phase, when effects on clinical endpoints or biomarkers may be expected Recent examples we have seen during MAD: Overweight/obese subjects (diabetes drug) Elderly subjects (drugs used for cognitive disorders) HCV or HIV patients (antivirals) Type II diabetes subjects (hypoglycemia agent) Asthmatic subjects (bronchodilator)
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Study Population
Age limits - Recent trends observed for studies conducted at Anapharm
Uper age limit typically based on safety considerations Elderly subjects may be considered if this is the target population
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Study Population
Should Females Be Enrolled in FIH Trials Regulatory position Most regulatory agencies have encouraged the enrolment of female subjects earlier in clinical development Safety considerations Despite the use of appropriate method of contraception, it may not always be safe to include women of childbearing potential Potential issue for long T drugs that remain in the body following the period of confinement within the Phase I unit Trends in recent studies that we have conducted Only 11% of the studies enrolled males only Females of childbearing potential were enrolled in 63% of studies that included females
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How Many Subjects Are Needed

No clear requirements from regulatory agencies Sample size rationale is most of the time not provided in protocols General consensus is that a minimum of 6 subjects should receive the active drug at each dose level and some subjects should receive a placebo Experience of Anapharm over the last two years In 67% of studies, each cohort included 6 patients on active treatment and 2 subjects on placebo Lowest number of subjects (on active treatment) per cohort was 3, while highest was 12 Number of cohorts (1 cohort per dose tested) varied from 4 to 12, with a mean of 7 cohorts
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How Many Subjects Are Needed

Statistical considerations
Minimum AE Incidence Needed to Observe at least one AE Occurrence (70%, 80% and 90% Probability) in a Treated Subjects Cohort
1 0.9 0.8
AE incidence
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
70% 80% 90%
Number of subjects on active treatment

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What Should be the Dose Escalation Approach

Case-by-case approach based on safety profile of the drug and potential risk Frequently used approaches: Classic approach using doubling scheme N, 2N, 4N, 8N, 16N, etc. Fibonacci scheme N, 2N, 3N, 5N, 8N, etc. Hybrid approach N, 2N, 4N, 6N, 10N, etc. Should be well justified to prevent questions from regulatory agencies or IRBs
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What Should be the Dose Escalation Approach

Experience of Anapharm over the last 2 years Lower dose ranges Doses increased in at least 2-fold icrement manner for 90% of the studies Higher dose ranges More conservative (e.g. Fibonacci) approach was used 63% of the time Examples of dose escalation schemes More conservative approach 100, 200, 300, 450, 600, 810, 100 mg MRSD was based on NOAEL with safety factor of 10 More aggressive approach 1, 3, 10, 30, 100, 300, 600 mg MRSD was based on MABEL (80 times < NOAEL/10) Interim blinded PK evaluation done before moving to the next cohort in about half the FIH studies Strongly recommended Page
16
Dosing Precautions Within A Cohort

Case-by-case approach based on safety profile of the drug, starting dose and potential risk Staggered dosing clearly recommended for high-risk compounds Approach often used: Dosing 2 subjects (e.g., 1 active and 1 placebo) at least 24 hours before remaining subjects of the cohort This strategy should ideally be used for all cohorts but is sometimes used only for first cohort(s) (with proper justification) Dosing may also be spread over the same day, e.g., first two subjects dosed 4 hours apart, on the same day Again, the dosing strategy within a cohort should always be well justified in protocol
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Dosing Precautions Within A Cohort

Staggered dosing was widely used for biologics and for injectable products
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Should We Use Parallel or Cross-Over Design

Parallel design is generally considered as a safer approach to SAD Phase I studies Unknown PK in human (unknown T ) Unknown PD properties in human (any possibility of prolonged or irreversible toxicity Safety population is larger (more subjects are exposed to the drug as compared to a cross-over approach) Cross-over design Limit the number of subjects that need to be recruited Allow a better assessment of PK linearity But increased risk of losing subjects, thereby limiting safety evaluation
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Mixed approach sometimes used Example: 2 or 3 different cohorts of subjects who will receive more than one dose
Parallel cohorts with cross-over dosing
From: Zhou Y. Choice of designs and doses for early phase trials. Fundam Clin Pharmacol 18 (2004) 373-8
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How Can We Make a Phase I Program More Efficient

New reality: Increased pressure for reducing cost of clinical development Need to obtain a proof-of-concept earlier in the drug development process Pressure for obtaining more information from a single trial More demands for Integrated Phase I protocols, such as: Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) within the same protocol Food effect arm Drug-drug interaction arm Cohorts of patients (in addition to healthy volunteers)
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Recent Trends Observed for Studies Conducted at Anapharm 44% of the FIH studies were integrated SAD/MAD studies 48% of the FIH studies included a PD evaluation 47% of the FIH studies performed with oral formulations included a food effect evaluation (usually in a cross-over) Other additional objectives more occasionally seen Effect in CYP2D6 poor metabolizers Drug-drug interaction evaluation
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Example of an Integrated FIH Protocol (SAD/MAD)

A Phase I, Single-Centre, Randomized, Double-Blind, Placebo-Controlled Study of YY-123 in Healthy Subjects and Patients Phase A: Single ascending doses (SAD): (Cohorts 1 to 5)
8 subjects (6 active/2 placebo) per cohort/dose 5 cohorts planned Food effect studies in 1 cohort in a cross-over fashion
Phase B: Multiple doses for 14 day (MAD): (Cohorts 7 to 11)

8 subjects (6 active/2 placebo) per cohort/dose 4 cohorts of healthy volunteers 1 cohort of patients with targeted indication
Phase B of the study planned to start after the 4th SAD cohort 1-2 weeks between each cohort
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Typical Time Course of a SAD-MAD Combo with IV arm and ISCV assessment arm
S, E-R 320 mg or Placebo Cohort 5 -D
SAD
S, E-R
160 mg or Placebo Cohort 4
-D
S, E-R
80 mg or Placebo Cohort 3 Period 1
80 mg or Placebo Period 2
-D
S, E-R S, E-R 40 mg or Placebo Cohort 2 80 mg or Placebo Cohort MD2 -D
160 mg or Placebo Cohort MD3
-D
S, E-R
Oral 20 mg or Placebo Cohort 1 Period 1
IV 20 mg or Placebo Period 2
S, E-R -D
-D
S, E-R
40 mg or Placebo Cohort MD1
-D
MAD
S = Screening; E = Enrollment, R = Randomization; D = Study Discharge Cohorts in SAD (n = 6): 4 active drug : 2 placebo, in MAD (n=12): 8 active drug : 4 placebo
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Pros and Cons of Integrated FIH Protocols

Pros: Cost and time saving Only one protocol to submit to regulatory agency and IRB Only one study planning Maximize amount of information obtained from a single clinical trial Cons (or challenges): Less experience from regulatory agencies and IRBs More complex studies from a logistic standpoint Not as much time for review process and decision making before MAD Need for flexible protocol and well defined safety measurements with clear stopping criteria according to the potential risks Increased risk of amendments during the course of the study Conclusions drawn from non optimally designed study
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Intensive QT Evaluation in Phase I Trial (SAD/MAD) Early detection of a cardiac safety (QT) issue can potentially save enormous time and resources spent on development of an unsafe drug ECG may be recorded and analyzed in Phase I with the same quality as in a thorough QT (TQT) study.
ECGs at multiple time points
Unique opportunity to study the effect on QT interval at doses higher than those that may eventually be studied in a formal TQT study If QT prolongation is observed, this may prompt the conduct of a TQT study earlier in the drug development process, or cessation of further development
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Example from Literature of Intensive QT Evaluation in FIH SAD with 6 cohorts of 8 volunteers (6 active / 2 placebo) In addition to standard screening and safety ECGs, each subject underwent 3 continuous 12-lead ECG recordings (13-hour duration each) on Day -1, Day 1 and Day 2 Automatic QT-interval measurements made at 63 time points (28 at baseline and 35 on treatment), with points most frequent between 2 and 3 hours (around expected Tmax) Data points were synchronized to allow calculation of time-matched differences from Day -1 baseline Placebo subjects of all cohorts were pooled
Ref: Near-Thorough QT Study as Part of a First-In-Man Study. Malik et al, Journal of Clinical Pharmacology, 2008;48:1146-1157
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Intensive QT Evaluation in Phase I Trial (SAD/MAD) We however must consider the following: No positive control (to establish assay sensitivity) Insufficient power to detect QTc prolongation of 5 ms, but data may allow PK-QTc modelling Absence of QT prolongation in Phase I would generally not preclude the need for a TQT study Data may be supportive for drugs usually not requiring a TQT study (e.g., large molecules and cytotoxic drugs)
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Questions on FIH Studies Frequently Asked by IRB

Justification of the time allowed between cohorts Justification of the time allowed between sentinels and main cohort Justification for the non-use of sentinel subjects Justification of the provision for starting the MAD before SAD cohorts are completed Dose escalation criteria (should be included in the protocol)
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Questions Frequently asked by Health Canada (TPD or BGT)

Clinical review Clarification/justification of the upper age limit Clarification regarding the selection of the starting dose Clarification regarding selection of doses, dose escalation scheme and stopping criteria Request for allowing more time between each cohort Request for allowing more time between dosing of each subject on the same day Clarification of the stopping rules
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Phase I and Special PK Studies Often Performed

First time in human, singleand multiple dose Pharmacokinetics BA/BE studies Dose proportionality studies Drug-drug interactions Mass balance/metabolism Food effective study Effect of age Effect of gender Renal impairment study Hepatic impairment PK/PD studies Effect on biomarkers Proof of concept (included in FIH if possible
Many Guidance documents are available from the different regulatory agencies to assist sponsors and CROs in the design and analysis of BA/BE and clinical pharmacology studies
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Conclusion
Sponsors must assure that they have a drug product really suitable for Phase I trials Safety must always prevail when designing Phase I program There is a trend for more complex integrated FIH study protocols There is room for creativity in designing Phase I studies; but approach used must assure safety of study participants and must be scientifically sound The Phase I study represents a unique opportunity to gather information about the study drug within a large range of doses Growing interest for intensive QT evaluation in FIH studies
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Acknowledgements
Jean-Franois Gagn, M.Sc. Manager, Protocol Writing Sector, Anapharm Stphane Lamouche, Ph.D Ass. Director, Drug Development & Regulatory Affairs, Anapharm Richard Larouche, B.Pharm, MD Director, Medical Affairs, Anapharm Annie Ouimet, M.Sc. Senior Regulatory Affairs Associate, Anapharm Eric Shink, Ph.D Senior Biostatistician, Anapharm Fethi Trabelsi, Ph.D Director, Scientific & Regulatory Affairs, Anapharm
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Designing Safe and Efficient Phase I Studies to Expedite Clinical Development

Experience You Can Trust

Study Design Issues

Attempts To Make Phase I Programs More Efficient

Experience You Can Trust

Are You Ready to Move to Phase I

1) H. Dubin, Drug Del. Technol., 2006

Experience You Can Trust

Using a Non Optimal Formulation in FIH Case Example

Experience You Can Trust

Formulations Used in Recent Studies Done at Anapharm

Powder in a bottle used in almost 50% of studies with oral administration

Experience You Can Trust

Are You Ready to Move to Phase I

Some possible advantages of a good Phase I formulation strategy

Experience You Can Trust

Objectives of Phase I Trials

Experience You Can Trust

Determination of Maximum Recommended Starting Dose

Experience You Can Trust

Determination of Maximum Recommended Starting Dose

Experience You Can Trust

Experience You Can Trust

Experience You Can Trust

Experience You Can Trust

How Many Subjects Are Needed

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How Many Subjects Are Needed

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

70% 80% 90%

Number of subjects on active treatment

Experience You Can Trust

What Should be the Dose Escalation Approach

Experience You Can Trust

What Should be the Dose Escalation Approach

2010 PharmaNet Development Group, Inc. All rights reserved.

Experience You Can Trust

Dosing Precautions Within A Cohort

Experience You Can Trust

Dosing Precautions Within A Cohort

Experience You Can Trust

Should We Use Parallel or Cross-Over Design

Experience You Can Trust

Should We Use Parallel or Cross-Over Design

Experience You Can Trust

Should We Use Parallel or Cross-Over Design

Experience You Can Trust

How Can We Make a Phase I Program More Efficient

Experience You Can Trust

How Can We Make a Phase I Program More Efficient

Experience You Can Trust

Example of an Integrated FIH Protocol (SAD/MAD)

Phase B: Multiple doses for 14 day (MAD): (Cohorts 7 to 11)

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160 mg or Placebo Cohort 4

80 mg or Placebo Cohort 3 Period 1

S, E-R S, E-R 40 mg or Placebo Cohort 2 80 mg or Placebo Cohort MD2 -D

160 mg or Placebo Cohort MD3

Oral 20 mg or Placebo Cohort 1 Period 1

40 mg or Placebo Cohort MD1

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Pros and Cons of Integrated FIH Protocols

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